Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent <i>Clostridioides difficile</i> Infection
Authors: Matthew D. Sims, Sahil Khanna, Paul Feuerstadt, Thomas J. Louie, Colleen R. Kelly, Edward S. Huang, Elizabeth L. Hohmann, Elaine E. L. Wang, Caterina Oneto, Stuart H. Cohen, Charles S. Berenson, Louis Korman, Christine Lee, Bret Lashner, Colleen S. Kraft, Mayur Ramesh, Michael Silverman, Darrell S. Pardi, Ananya De, Asli Memisoglu, David A. Lombardi, Brooke R. Hasson, Barbara H. McGovern, Lisa von Moltke, Anmar Hemaidan, Princy Kumar, Bharat Misra, Richard Nathan, Hien Nguyen, John Pullman, Jeffrey Williams, Idalia Acosta, Alberto Odio, Huy Tran, Kent Smith, Leonard Weinstock, Val Hansen, Michael Georgetson, Aasim Sheikh, Julia Garcia-Diaz, Calin Arimie, Gladys Andrade, Steven O'Marro, Tuba Esfandyari, Timothy Ritter, Ian Mcnicol Baird, Ronald Colman, Meenakshi Patel, Lilliam Hernandez, Atoya Adams, Marie Walton, Razvan Arsenescu, Max Shapiro, Paul Cook, Marvin Heuer, Tatiana Bogdanovich, Doria Grimard, Theodore Steiner, Debra Butt, Peter Daley, Stephanie Gauthier, Chantal Guimont, Michael Kreines, Larry Berman, Michael Bennett, Ronald Fogel, Juan Carlos Moises Gutierrez, Peder Pedersen, Adam Bressler, Venkatesh Nadar, Eric Newton, Jorge Diaz, Jalal Abbas, Herbert DuPont, Aamir Jamal, Neetu Talreja, Sabrina Benjamin, Kamran Ayub, Godson Oguchi, Jose Pinero, Gowrappala Ramesh, Paul Sepe, Loren Brook, Frederick Ruthardt, Lindsey Surace, Ayub Hussain, Travis Rutland, Micahel Schmalz, Gourisankar Degala, Raymond Phillips, Kent Stock, Jeffrey Bullock, Kenolisa Onwueme
Journal: JAMA Network Open (2023)

Importance A safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence. Objectives To evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks. Design, Setting, and Participants This phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry. Interventions SER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI. Main Outcomes and Measures The main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population. Results Of 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]). Conclusions and Relevance In this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI. Trial Registration ClinicalTrials.gov identifier: NCT03183141